Natural Killer (NK) cells play an important role in the control of viral infection before the establishment of a specific cytolytic T cell response mediated by CD3-positive MHC-restricted T cells. NK cells are also involved in the rejection of bone marrow transplants. Natural Killer cells kill target cells unless they receive a negative signal from a receptor that recognizes MHC class I molecule on target cells. The Section discovered that recognition of HLA-B27 molecules by human NK clones was not only peptide-dependent, but also peptide-specific. This provides a new conceptual framework in which to study the complex recognition of virus-infected cells by NK clones. In addition, the Section has isolated molecular clones for a family of inhibitory NK receptors involved in the recognition of HLA-C alleles. Surprisingly, these NK receptors belong to the immunoglobulin superfamily and exhibit an interesting type of dual diversity. In addition to sequence differences in the extracellular domains, these receptors exist with different types of cytoplasmic tails, even on molecules that have closely related Ig domains. A functional reconstitution system was developed and used to demonstrate that individual receptors with the longer form of cytoplasmic tail provided both the specificity for MHC class I molecules on target cells, and the negative signal that inhibits NK-mediated lysis of target cells.